Abstract

The metabotropic GABAB and adenosine A1 receptors mediate presynaptic inhibition through regulation of voltage-dependent Ca2+ channels, whereas K+ channel regulation is believed to have no role at the CA3-CA1 synapse. We show here that the inhibitory effect of baclofen (20 μM) and adenosine (300 μM) on field EPSPs are differentially sensitive to Cs+ (3.5 mM) and Ba2+ (200 μM), but not 4-aminopyridine (100 μM). Barium had no effect on paired-pulse facilitation (PPF) in itself, but gave significant reduction (14 ± 5%) when applied in the presence of baclofen, but not adenosine, suggesting that the effect is presynaptic and selective on the GABAB receptor-mediated response. The effect of Ba2+ on PPF was not mimicked by tertiapin (30 nM), indicating that the underlying mechanism does not involve GIRK channels. Barium did not affect PPF in slices from young rats (P7–P8), suggesting developmental regulation. The above effects of Ba2+ on adult tissue were reproduced when measuring evoked whole-cell EPSCs from CA1 pyramidal neurons: PPF was reduced by 22 ± 3% in the presence of baclofen and unaltered in adenosine. In contrast, Ba2+ caused no significant change in frequency or amplitude of miniature EPSCs. The Ba2+-induced reduction of PPF was antagonized by LY341495, suggesting metabotropic glutamate receptor involvement. We propose that these novel effects of Ba2+ and Cs+ are exerted through blockade of inwardly rectifying K+ channels in glial cells, which are functionally interacting with the GABAB receptor-dependent glutamate release that generates heterosynaptic depression.

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Acknowledgments

The authors would like to express their gratitude to Bertha P. B. Mortensen, Alison Margolis, and Gaston Calfa for invaluable technical assistance and advice. This project was supported by grants from The Lundbeck Foundation, The Brd. Hartmanns Foundation, The Aase og Ejnar Danielsens Foundation, The A.P. Møller Foundation for the Advancement of Medical Science, The Danish Medical Research Council, and by grant no NS22373 (JJH).